Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Updating the evidence for an association between anxiety and risk of Alzheimer's disease: A meta-analysis of prospective cohort studies.

OBJECTIVES: Anxiety is postulated to be a modifiable risk factor for Alzheimer's disease (AD). Our primary aim was to conduct a meta-analysis of prospective cohort studies investigating the association between anxiety and AD risk. DESIGN: We searched multiple scientific databases to identify relevant papers published up to March 2019. Inclusion criteria were: prospective cohort studies with a minimum follow-up period of 1 year, baseline anxiety assessment, absence of dementia at baseline, investigated the association between anxiety and AD incidence, and reporting Relative Risks (RRs), or equivalents (HRs and SHRs), for the association between anxiety and AD risk. We excluded studies that: focused on subjective memory or mild cognitive impairment samples, review and meta-analyses, not reporting original, published peer-reviewed results. We used a random-effects model that accommodated the differences in association statistics. RESULTS: 7 prospective cohorts (reported in 6 studies), with a total of 24,528 participants, were included in our meta-analysis. A marginally significant association between anxiety and AD risk was found, with a pooled RR of 1.45 (95% CI: 1.00-2.12), and a population attributable fraction for AD of 2.8% (95% CI: 1.2%-4.3%). LIMITATIONS: There was a high level of heterogeneity across the studies, which may be associated with differences in the covariates adjusted for. Studies also differed considerably in how they measured anxiety. CONCLUSION: Anxiety is marginally associated with an increased risk of AD in this meta-analysis. Future research is needed to determine the extent to which anxiety might be a cause of AD rather than a prodrome or marker.

The Vascular Behavioral and Cognitive Disorders criteria for vascular cognitive disorders: a validation study.

BACKGROUND AND PURPOSE: The Vascular Behavioral and Cognitive Disorders (VASCOG) criteria for vascular cognitive disorders were published in 2014, but their concurrent and predictive validity have not been examined. METHODS: Participants (N = 165, aged 49-86 years) were from Sydney Stroke Study, a longitudinal study of post-stroke cognitive impairment and dementia. Diagnoses using the National Institute of Neurological Disorders and Stroke - Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN), the Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for vascular dementia (VaD) were made by consensus at multidisciplinary case conferences. Diagnoses for mild vascular cognitive disorder (mVCD) and VaD using VASCOG, DSM-5 and the Vascular Impairment of Cognition Classification Consensus Study (VICCCS) criteria were made by two study authors. Agreement levels between criteria sets were examined using Cohen's kappa (κ). The ability of VaD diagnoses to predict mortality over 10 years and of mVCD to predict dementia over 5 years was investigated. RESULTS: The VASCOG criteria yielded rates of mVCD slightly lower than for DSM-5 and VICCCS. VaD rates were similar for all criteria, although slightly lower for DSM-IV. Agreement between the VASCOG, VICCCS and DSM-5 criteria was excellent for VaD and mVCD (κ = 0.83-1.0), but lower for VaD between VASCOG and the other criteria (κ = 0.47-0.63). VaD-based mortality predictions were similar for the VASCOG, VICCCS and DSM-5 criteria, and higher than those for other criteria. The prediction of incident dementia within 5 years from mVCD was slightly lower with VASCOG criteria than with DSM-5 and VICCCS criteria. CONCLUSIONS: The VASCOG criteria have greater sensitivity, modest concurrent validity and better predictive validity than older criteria for VaD, but are comparable to DSM-5 and VICCCS criteria. Their operationalization and inclusion of a mild VCD category make them useful for clinical and research applications.

Auditory verbal hallucinations are related to cortical thinning in the left middle temporal gyrus of patients with schizophrenia.

BACKGROUND: Auditory verbal hallucinations (AVHs) are one of the most common and severe symptoms of schizophrenia, but the neuroanatomical abnormalities underlying AVHs are not well understood. The present study aims to investigate whether AVHs are associated with cortical thinning. METHODS: Participants were schizophrenia patients from four centers across China, 115 with AVHs and 93 without AVHs, as well as 261 healthy controls. All received 3 T T1-weighted brain scans, and whole brain vertex-wise cortical thickness was compared across groups. Correlations between AVH severity and cortical thickness were also determined. RESULTS: The left middle part of the middle temporal gyrus (MTG) was significantly thinner in schizophrenia patients with AVHs than in patients without AVHs and healthy controls. Inferences were made using a false discovery rate approach with a threshold at p < 0.05. Left MTG thickness did not differ between patients without AVHs and controls. These results were replicated by a meta-analysis showing them to be consistent across the four centers. Cortical thickness of the left MTG was also found to be inversely correlated with hallucination severity across all schizophrenia patients. CONCLUSION: The results of this multi-center study suggest that an abnormally thin left MTG could be involved in the pathogenesis of AVHs in schizophrenia.

Convergence of parvocellular and magnocellular information channels in the primary visual cortex of the macaque.

We investigated whether responses of single cells in the striate cortex of anaesthetized macaque monkeys exhibit signatures of both parvocellular (P) and magnocellular (M) inputs from the dorsal lateral geniculate nucleus (dLGN). We used a palette of 128 isoluminant hues at four different saturation levels to test responses to chromatic stimuli against a white background. Spectral selectivity with these isoluminant stimuli was taken as an indication of P inputs. The presence of magnocellular inputs to a given cortical cell was deduced from its responses to a battery of tests, including assessment of achromatic contrast sensitivity, relative strengths of chromatic and luminance borders in driving the cell at different velocities and conduction velocity of their retino-geniculo-cortical afferents. At least a quarter of the cells in our cortical sample appear to receive convergent P and M inputs. We cannot however, exclude the possibility that some of these cells could be receiving a convergent input from the third parallel channel from the dLGN, namely the koniocellular (K) rather than the P channel. The neurons with convergent P and M inputs were recorded not only from supragranular and infragranular layers but also from the principal geniculate input recipient layer 4. Thus, our results challenge classical ideas of strict parallelism between different information streams at the level of the primate striate cortex.

Repeated local administration of noradrenaline or saline inhibits thermal hyperalgesia in pain-sensitized human skin.

AIMS: Noradrenaline increases thermal hyperalgesia in skin sensitized to heat by the topical application of capsaicin. The aim of this study was to determine whether desensitization to the hyperalgesic effects of noradrenaline would develop after repeated local administrations of noradrenaline in the skin of the forearm. METHODS: Noradrenaline and saline were administered to the forearm by iontophoresis (200 microA, 2 min, over a surface area of 3.1 cm(2)) two times per day for 4-10 days in 19 healthy subjects. The adequacy of the desensitization procedure was evaluated by measuring noradrenaline-induced vasoconstriction with laser Doppler fluxmetry. Thresholds and pain ratings to heat were then investigated at treated and control sites before and after the topical application of capsaicin, and after the iontophoresis of noradrenaline. RESULTS: At previously untreated sites blood flow was 49 +/- 14% (+/- 95% confidence intervals) lower than flow at reference sites after the iontophoresis of noradrenaline. Vascular signs of adrenergic desensitization developed after 4-5 days of repeated local administration of noradrenaline in the majority of subjects. In those whose vessels constricted after the acute administration of noradrenaline, the adrenergic response averaged 23 +/- 15% at the desensitized site compared with 61 +/- 9% at previously untreated sites (P < 0.001). However, similar signs developed after repeated iontophoreses of saline (adrenergic response 7 +/- 16% compared with 58 +/- 15% at previously untreated sites, P < 0.001). Both the noradrenaline and saline treatments inhibited thermal hyperalgesia after the topical application of capsaicin. Heat-pain thresholds averaged 43.2 +/- 2.5 degrees C and 43.0 +/- 2.3 degrees C at the noradrenaline and saline pretreated sites compared with 41.4 +/- 2.7 degrees C at the control site (P < 0.05 and P < 0.06, respectively). On a 0-10 scale, heat-pain ratings to a 7 s, 45 degrees C stimulus averaged 3.8 +/- 1.6 and 3.5 +/- 1.7 at the noradrenaline and saline pretreated sites compared with 5.3 +/- 1.6 at the control site (P < 0.05). After the iontophoresis of noradrenaline heat-pain ratings increased 1.6 +/- 1.4 at the site pretreated with saline (P < 0.05) compared with only 0.4 +/- 1.0 at the site pretreated with noradrenaline (not significant), consistent with local adrenergic desensitization. CONCLUSIONS: We conclude that repeated iontophoreses of noradrenaline or saline inhibit vasoconstriction to noradrenaline, and also inhibit increases in thermal hyperalgesia evoked by capsaicin. The release of endogenous stores of noradrenaline by iontophoretic currents might contribute to these effects.

Facilitating laser Doppler measurements of cutaneous adrenergic vasoconstriction: a comparison of methods.

Detecting vasoconstriction in the skin of the human forearm is often difficult because cutaneous perfusion is usually low, even in the absence of vasoconstrictive agents. However, flow through "vasoconstricted" skin can be detected by increasing the background skin blood flow. The aim of the current study was to evaluate local warming and postocdusive reactive hyperemia as techniques for increasing background flow to facilitate laser Doppler measurements of cutaneous vasoconstriction in the forearm. Noradrenaline introduced by iontophoresis into the forearm of healthy volunteers initially reduced the peak hyperemic response (mean decrease in hyperemia 21 +/- 7%, p <0.01), compared with a saline control. However, vasoconstriction was unrelated to the dose of noradrenaline and was not detectable when the test was repeated, possibly because the peak of the normal hyperemic response decreased with repeated occlusions. When the forearm was warmed to 42 degrees C, noradrenaline introduced by iontophoresis produced dose-dependent vasoconstriction relative to saline control sites and skin not having undergone iontophoresis (greatest mean decrease 64 +/- 7%, p <0.001). Therefore, local warming is recommended over reactive hyperemia for facilitating laser Doppler recordings of cutaneous vasoconstriction in the human forearm.

Vascular and nociceptive effects of localized prolonged sympathetic blockade in human skin.

Supersensitivity to noradrenaline contributes to certain vascular disorders (e.g., hypertension) and chronic neuropathic pain conditions (e.g., complex regional pain syndrome). We aimed to develop a procedure for inducing adrenergic supersensitivity that could be used to investigate the role of catecholamines in these clinical conditions. In the first study, three doses of guanethidine were administered by iontophoresis to separate small patches of skin in the forearm of healthy human volunteers. Four to five hours later. the vasoconstrictor response to the adrenergic releasing agent tyramine was inhibited in a dose-dependent manner by iontophoretic pretreatment with guanethidine, indicating that guanethidine had depleted endogenous adrenergic stores. In a second study, guanethidine and saline were administered by iontophoresis four times over approximately 2 weeks at separate sites in the forearm. One to two days after the final pretreatment, vasoconstriction to the iontophoresis of a weak dose of noradrenaline was enhanced at sites pretreated with guanethidine. To investigate the effect of guanethidine pretreatment on thermal hyperalgesia. the experimental sites were sensitized to heat by the topical application of 0.6% capsaicin. Both before and after the application of capsaicin, the heat-pain threshold and heat-pain ratings to suprathreshold stimulation were similar at sites pretreated for 2 weeks with guanethidine or saline. However, after the iontophoresis of noradrenaline, thermal hyperalgesia was greater at the guanethidine-pretreated site than the saline pretreated site. These observations indicate that prolonged depletion of adrenergic stores by guanethidine induces adrenergic supersensitivity in cutaneous vessels, and that adrenergic supersensitivity enhances thermal hyperalgesia in the presence of noradrenaline.

Noradrenaline provokes axon reflex hyperaemia in the skin of the human forearm.

High doses of noradrenaline increase the sensitivity of skin to heat, presumably by sensitizing nociceptive afferent fibres. Since activation of these fibres increases local blood flow by an axon reflex mechanism, noradrenaline might simultaneously evoke adrenoceptor-mediated vasoconstriction and axon reflex vasodilatation. To investigate this possibility, noradrenaline was introduced into the skin of the human forearm by iontophoresis, and changes in blood flow were monitored in nearby skin. Increases in blood flow were greater near the site of noradrenaline iontophoresis than near the site of saline iontophoresis. Since the response was limited in its distribution to a few centimeters from the site of iontophoresis, hyperaemia was most likely due to a local mechanism rather than a spinal or supraspinal reflex. In addition, pretreatment of the skin with a local anaesthetic cream inhibited the increase in flow, indicating that the response was mediated neurally. These findings suggest that activation of nociceptive afferents by noradrenaline provokes axon reflex hyperaemia.